Journal article

BCL-XL is an actionable target for treatment of malignant pleural mesothelioma

Surein Arulananda, Megan O'Brien, Marco Evangelista, Tiffany J Harris, Nikita S Steinohrt, Laura J Jenkins, Marzena Walkiewicz, Robert JJ O'Donoghue, Ashleigh R Poh, Bibhusal Thapa, David S Williams, Trishe Leong, John M Mariadason, Xia Li, Jonathan Cebon, Erinna F Lee, Thomas John, W Douglas Fairlie

CELL DEATH DISCOVERY | SPRINGERNATURE | Published : 2020

Abstract

Despite having one of the lowest survival rates of all cancers, there have been no new approved treatments for malignant pleural mesothelioma (MPM) in over a decade. Standard-of-care treatment relies on Cisplatin plus Pemetrexed chemotherapy. Here, we tested a suite of BH3-mimetic drugs targeting BCL-2 pro-survival proteins of the intrinsic apoptotic pathway. We found BCL-XL is the dominant pro-survival protein in a panel of cell lines in vitro, though potent, synergistic cell killing occurred with MCL-1 co-targeting. This correlates with high-level expression of BCL-XL and MCL-1 in cell lines and a large cohort of patient tumour samples. BCL-XL inhibition combined with Cisplatin also enhanc..

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Grants

Awarded by National Health and Medical Research Council of Australia


Awarded by Tour de Cure Pioneering Grant


Awarded by Australian Research Council


Awarded by Victorian Cancer Agency (Mid-Career Fellowship)


Funding Acknowledgements

Support for this work was provided by the National Health and Medical Research Council of Australia Project Grant (GNT1157551) and Tour de Cure Pioneering Grant (RSP-202-18/19) to W.D.F. and T.J., Senior Research Fellowship (GNT1046092) to J.M.M. and Peter Doherty Early Career Fellowship (GNT1166447) to A.R.P. S.A. and L.J.J. are the recipients of a La Trobe University Post Graduate Research Scholarship and S.A. a Lung Foundation Australia Grant-in-Aid. E.F.L. is a recipient of fellowships from the Australian Research Council (Future Fellowship FT150100212) and the Victorian Cancer Agency (Mid-Career Fellowship MCRF19045). We thank Mr. Josh Lorimer and Ms. Haley Sleep from the Austin Health Bio Resources Facility for providing technical mouse work support. We are grateful to Mr. David Baloyan for his technical expertise with FACS-based assays and sorting.